Clinical trial NCT00109707: A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies
Official title: A Phase IA/II Multicenter, Dose-escalation Study of Oral AMN107 on a Continuous Daily Dosing Schedule in Adult Patients With Imatinib-resistant/Intolerant CML in Chronic or Accelerated Phase or Blast Crisis, Relapsed/Refractory Ph+ ALL, and Other Hematologic Malignancies.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Chronic Myelogenous Leukemia
Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive)
Hypereosinophilic Syndrome
Systemic Mastocytosis
Keywords: CML in blast crisis
CML in chronic phase
CML in accelerated phase
Gleevec resistance
Gleevec intolerant
Gleevec and CML
imatinib resistance
imatinib intolerant
Hypereosinophilic Syndrome
Systemic Mastocytosis
Chronic eosinophilic syndrome
Philadelphia chromosome positive acute lymphoblastic leukemia
HES
CEL
CML
SM
Ph+ ALL refractory to standard therapy
Ph+ALL relapsed
AMN107A
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2005-05-03
Enrollment: 507
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this trial is to assess the efficacy, safety, tolerability, biologic activity, and pharmacokinetics of AMN107 in six groups of patients with one of the following conditions:

Relapsed/refractory Ph+ Acute lymphoblastic leukemia (ALL) (arm 1)

Group A - Imatinib failure only (arms 2, 3 and 4)

* imatinib-resistant or intolerant CML - Chronic Phase (CP)
* imatinib-resistant or intolerant CML - Accelerated Phase (AP)
* imatinib-resistant or intolerant CML - Blast Crisis (BC)

Group B - Imatinib and other TKI failure (arms 2, 3 and 4)

* imatinib-resistant or intolerant CML - Chronic Phase (CP)
* imatinib-resistant or intolerant CML - Accelerated Phase (AP)
* imatinib-resistant or intolerant CML - Blast Crisis (BC)

Hypereosinophilic syndrome/chronic eosinophilic leukemia (HES/CEL) (arm 5)

Systemic mastocytosis (Sm) (arm 6)


Eligibility criteria: Inclusion Criteria:

Main inclusion criteria include:

* Patients with CML in blast crisis, CML in accelerated phase defined as never in blast crisis phase, or CML in chronic phase defined as never been in blast crisis phase or accelerated phase who have: \*developed progressive disease during therapy with at least 600 mg of imatinib per day, -OR- \*patients with CML on imatinib therapy, at any dose, developing progressive disease and the presence of a genetic mutation likely to result in imatinib resistance -OR- \*have developed an intolerance to imatinib
* Relapsed or refractory Ph+ ALL
* Hypereosinophilic syndrome/chronic eosinophilic leukemia.
* Systemic mastocytosis who have a clinical indication for treatment.
* Prior imatinib therapy for patients with Ph+ ALL, HES/CEL and SM is permitted but is not required
* CML patients who have been treated with an investigational tyrosine kinase inhibitor who otherwise meet the definition of imatinib-resistance or intolerance are eligible
* Written informed consent prior to any study procedures being performed

Exclusion Criteria:

* Impaired cardiac function
* Patients with severe/chronic or uncontrolled medical conditions (including but not limited to diabetes, infections, GI impairment, CNS infiltration, liver and kidney disease)
* Prior and concomitant use of certain medications (including but not limited to warfarin, chemotherapy, hematopoietic colony-stimulating growth factors, medications that can affect electrocardiogram test results, other investigational drugs )
* Women who are pregnant or breastfeeding
* Patients with a history of another primary malignancy that is currently clinically significant or currently requires active intervention.
* Patients unwilling to comply with the protocol.
* Known diagnosis of human immunodeficiency virus (HIV) infection

Other protocol-defined inclusion/exclusion criteria may apply

Primary outcomes:
measure: Number of Participants With Major Cytogenetic Response (MCyR)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
measure: Number of Participants Confirmed Overall Hematological Response (Phase II)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
Secondary outcomes:
measure: Number of Participants With Overall Major Cytogenetic Responses (Phase II)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
measure: Number of Participants With Complete Hematologic Response (Phase II)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
measure: Participants With (MMR) Major Molecular Response (Phase II)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
measure: Time to Progression (TTP) (Phase II)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
measure: Overall Survival (OS) (Phase II)
timeFrame: Up to End of the Treatment (Approximately 7.5 years)
measure: Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety
timeFrame: From First Participant First Visit to Last Participant Last Visit (Approximately 7.5 years)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Tampa
country: United States
facility: H. Lee Moffitt Cancer Center & Research Institute Dept.of H. Lee Moffitt
state: Florida
city: Chicago
country: United States
facility: University of Chicago Medical Center Dept. of U. of Chicago Hosp(3)
state: Illinois
city: Chicago
country: United States
facility: University of Illinois at Chicago Divisionof Hematology/Oncology
state: Illinois
city: Beech Grove
country: United States
facility: Indiana Blood and Marrow Institute Dept of Indiana Blood&Mar (2)
state: Indiana
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Div.of Hematologic Malignancie
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System Clinical Trials Office
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute Rosewell SC
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Baptist Medical Center
state: North Carolina
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Germantown
country: United States
facility: The Jones Clinic
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University Medical Center, Clinical Trials Center Investigational Drug Services
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center/University of Texas
state: Texas
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: St. Leonards
country: Australia
facility: Novartis Investigative Site
state: New South Wales
city: Adelaide
country: Australia
facility: Novartis Investigative Site
state: South Australia
city: Prahran
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Haine-saint-Paul
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Yvoir
country: Belgium
facility: Novartis Investigative Site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Toronto
country: Canada
facility: Novartis Investigative Site
state: Ontario
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Montreal
country: Canada
facility: Novartis Investigative Site
state: Quebec
city: Vejle
country: Denmark
facility: Novartis Investigative Site
city: HUS Helsinki
country: Finland
facility: Novartis Investigative Site
city: Bordeaux Cedex
country: France
facility: Novartis Investigative Site
city: Créteil
country: France
facility: Novartis Investigative Site
city: Dijon
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Limoges cedex
country: France
facility: Novartis Investigative Site
city: Lyon
country: France
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Poitiers
country: France
facility: Novartis Investigative Site
city: Rennes
country: France
facility: Novartis Investigative Site
city: Vandoeuvre les Nancy
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Duesseldorf
country: Germany
facility: Novartis Investigative Site
city: Frankfurt/M
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Leipzig
country: Germany
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Mannheim
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Pokfulam
country: Hong Kong
facility: Novartis Investigative Site
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Genova
country: Italy
facility: Novartis Investigative Site
state: GE
city: Monza
country: Italy
facility: Novartis Investigative Site
state: MB
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Pescara
country: Italy
facility: Novartis Investigative Site
state: PE
city: Pavia
country: Italy
facility: Novartis Investigative Site
state: PV
city: Reggio Calabria
country: Italy
facility: Novartis Investigative Site
state: RC
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Roma
country: Italy
facility: Novartis Investigative Site
state: RM
city: Orbassano
country: Italy
facility: Novartis Investigative Site
state: TO
city: Napoli
country: Italy
facility: Novartis Investigative Site
city: Hwasun-gun
country: Korea, Republic of
facility: Novartis Investigative Site
state: Jeollanam-do
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Taegu
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Grafton
country: New Zealand
facility: Novartis Investigative Site
state: Auckland
city: Oslo
country: Norway
facility: Novartis Investigative Site
city: Katowice
country: Poland
facility: Novartis Investigative Site
city: Lodz
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Warszawa
country: Poland
facility: Novartis Investigative Site
city: Wroclaw
country: Poland
facility: Novartis Investigative Site
city: Singapore
country: Singapore
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Göteborg
country: Sweden
facility: Novartis Investigative Site
city: Linköping
country: Sweden
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Basel
country: Switzerland
facility: Novartis Investigative Site
city: Genève
country: Switzerland
facility: Novartis Investigative Site
city: Niaosong Township
country: Taiwan
facility: Novartis Investigative Site
city: Birmingham
country: United Kingdom
facility: Novartis Investigative Site
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Glasgow - Scotland
country: United Kingdom
facility: Novartis Investigative Site
city: Leeds
country: United Kingdom
facility: Novartis Investigative Site
city: Liverpool
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticlas
role: STUDY_DIRECTOR
References:
citation: Hochhaus A, Baccarani M, Giles FJ, le Coutre PD, Muller MC, Reiter A, Santanastasio H, Leung M, Novick S, Kantarjian HM. Nilotinib in patients with systemic mastocytosis: analysis of the phase 2, open-label, single-arm nilotinib registration study. J Cancer Res Clin Oncol. 2015 Nov;141(11):2047-60. doi: 10.1007/s00432-015-1988-0. Epub 2015 May 23.
citation: Hochhaus A, le Coutre PD, Kantarjian HM, Baccarani M, Erben P, Reiter A, McCulloch T, Fan X, Novick S, Giles FJ. Effect of the tyrosine kinase inhibitor nilotinib in patients with hypereosinophilic syndrome/chronic eosinophilic leukemia: analysis of the phase 2, open-label, single-arm A2101 study. J Cancer Res Clin Oncol. 2013 Dec;139(12):1985-93. doi: 10.1007/s00432-013-1529-7. Epub 2013 Sep 22.
citation: Stein AM, Martinelli G, Hughes TP, Muller MC, Beppu L, Gottardi E, Branford S, Soverini S, Woodman RC, Hochhaus A, Kim DW, Saglio G, Radich JP. Rapid initial decline in BCR-ABL1 is associated with superior responses to second-line nilotinib in patients with chronic-phase chronic myeloid leukemia. BMC Cancer. 2013 Apr 2;13:173. doi: 10.1186/1471-2407-13-173.
citation: Kantarjian HM, Giles FJ, Bhalla KN, Pinilla-Ibarz J, Larson RA, Gattermann N, Ottmann OG, Hochhaus A, Radich JP, Saglio G, Hughes TP, Martinelli G, Kim DW, Shou Y, Gallagher NJ, Blakesley R, Baccarani M, Cortes J, le Coutre PD. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2011 Jan 27;117(4):1141-5. doi: 10.1182/blood-2010-03-277152. Epub 2010 Nov 22.
citation: Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, Ossenkoppele GJ, Nicolini FE, O'Brien SG, Litzow M, Bhatia R, Cervantes F, Haque A, Shou Y, Resta DJ, Weitzman A, Hochhaus A, le Coutre P. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007 Nov 15;110(10):3540-6. doi: 10.1182/blood-2007-03-080689. Epub 2007 Aug 22.
citation: Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. doi: 10.1056/NEJMoa055104.