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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

Primary Purpose

Philadelphia Chromosome Positive Chronic Myelogenous Leukemia

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

Nilotinib + LDE225

About this trial

This is an interventional treatment trial for Philadelphia Chromosome Positive Chronic Myelogenous Leukemia focused on measuring LDE225, nilotinib, Chronic myeloid leukemia, CML, Philadelphia positive, Ph+, resistant, Resistant Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP)

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Philadelphia chromosome positive (Ph+) CML in chronic phase (CP) or accelerated phase (AP)with resistance to at least one prior BCR-ABL targeting TKI
Documented chronic phase CML
Adequate end organ function
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:

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

Other protocol-defined inclusion/exclusion criteria may apply.

Sites / Locations

Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site
Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Nilotinib + LDE225

Arm Description

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

Outcomes

Primary Outcome Measures

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

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

Assessment of the safety and tolerability profile of nilotinib in combination with LDE225

Plasma concentration and basic pharmacokinetics (PK) parameters (as Cmax, Tmax, AUC)

Assessment of the PK characteristics of nilotinib administered in combination with LDE225

Major molecular response (MMR) rates at 3, 6 and 12 months

Determination of the kinetics of major molecular response

Complete molecular response (CMR) rates at 3, 6 and 12 months

Determination of the kinetics of complete molecular response

Major cytogenic response (MCyR) rates by 3, 6 and 12 months

Determination of major cytogenetic response rates

Complete cytogenic response (CCyR) rates by 3, 6 and 12 months

Determination of complete cytogenetic response rates

Full Information

NCT ID

NCT01456676

First Posted

October 14, 2011

Last Updated

December 6, 2020

Sponsor

Novartis Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT01456676

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2016

Overall Recruitment Status

Completed

Study Start Date

January 2012 (undefined)

Primary Completion Date

February 2014 (Actual)

Study Completion Date

February 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Novartis Pharmaceuticals

4. Oversight

5. Study Description

Brief Summary

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Philadelphia Chromosome Positive Chronic Myelogenous Leukemia

Keywords

LDE225, nilotinib, Chronic myeloid leukemia, CML, Philadelphia positive, Ph+, resistant, Resistant Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP)

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Nilotinib + LDE225

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Nilotinib + LDE225

Intervention Description

Nilotinib is an aminopyrimidine ATP-competitive inhibitor of the protein tyrosine kinaseactivity of BCR-ABL.

Primary Outcome Measure Information:

Title

Incidence rate and category of dose limiting toxicities (DLTs) during the first two cycles of therapy

Description

Determination of the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of nilotinib in combination with LDE225

Time Frame

56 days (2 treatment cycles at 28 days each)

Secondary Outcome Measure Information:

Title

Description

Assessment of the safety and tolerability profile of nilotinib in combination with LDE225

Time Frame

336 days (12 treatment cycles)

Title

Plasma concentration and basic pharmacokinetics (PK) parameters (as Cmax, Tmax, AUC)

Description

Assessment of the PK characteristics of nilotinib administered in combination with LDE225

Time Frame

50 days

Title

Major molecular response (MMR) rates at 3, 6 and 12 months

Description

Determination of the kinetics of major molecular response

Time Frame

336 days (12 treatment cycles)

Title

Complete molecular response (CMR) rates at 3, 6 and 12 months

Description

Determination of the kinetics of complete molecular response

Time Frame

336 days (12 treatment cycles)

Title

Major cytogenic response (MCyR) rates by 3, 6 and 12 months

Description

Determination of major cytogenetic response rates

Time Frame

336 days (12 treatment cycles)

Title

Complete cytogenic response (CCyR) rates by 3, 6 and 12 months

Description

Determination of complete cytogenetic response rates

Time Frame

336 days (12 treatment cycles)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Philadelphia chromosome positive (Ph+) CML in chronic phase (CP) or accelerated phase (AP)with resistance to at least one prior BCR-ABL targeting TKI Documented chronic phase CML Adequate end organ function 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: Impaired cardiac function Severe and/or uncontrolled concurrent disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis 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 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. Previously documented BCR-ABL Y253H, E255K/V, T315I or F359C/V mutation Other protocol-defined inclusion/exclusion criteria may apply.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Novartis Pharmaceuticals

Organizational Affiliation

Novartis Pharmaceuticals

Official's Role

Study Director

Facility Information:

Facility Name

Novartis Investigative Site

City

Toronto

State/Province

Ontario

ZIP/Postal Code

M5G 2M9

Country

Canada

Facility Name

Novartis Investigative Site

City

Marseille

ZIP/Postal Code

13273

Country

France

Facility Name

Novartis Investigative Site

City

Frankfurt

ZIP/Postal Code

60590

Country

Germany

Facility Name

Novartis Investigative Site

City

Ulm

ZIP/Postal Code

89081

Country

Germany

Facility Name

Novartis Investigative Site

City

Roma

State/Province

ZIP/Postal Code

00161

Country

Italy

Facility Name

Novartis Investigative Site

City

Pamplona

State/Province

Navarra

ZIP/Postal Code

31008

Country

Spain

Facility Name

Novartis Investigative Site

City

Madrid

ZIP/Postal Code

28006

Country

Spain

12. IPD Sharing Statement

Links:

URL

https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=13103

Description

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

Learn more about this trial

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

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