A Study of Oral AMN107 in Adults With Chronic Myelogenous Leukemia (CML) or Other Hematologic Malignancies

Chronic Myelogenous Leukemia Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00109707
• Other study ID #: CAMN107A2101
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: April 2005
• Est. completion date: September 2012

Study information

• Verified date: June 2021
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 507
• Est. completion date: September 2012
• Est. primary completion date: September 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia (Philadelphia Chromosome Positive)
• Chronic Myelogenous Leukemia
• Hematologic Neoplasms
• Hypereosinophilic Syndrome
• Leukemia
• Leukemia, Lymphoid
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Mastocytosis
• Philadelphia Chromosome
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Syndrome
• Systemic Mastocytosis

Intervention

Drug:
• Nilotinib

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Adelaide	South Australia
Australia	Novartis Investigative Site	Prahran	Victoria
Australia	Novartis Investigative Site	St. Leonards	New South Wales
Austria	Novartis Investigative Site	Wien
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Haine-saint-Paul
Belgium	Novartis Investigative Site	Leuven
Belgium	Novartis Investigative Site	Yvoir
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
Canada	Novartis Investigative Site	Vancouver	British Columbia
Denmark	Novartis Investigative Site	Vejle
Finland	Novartis Investigative Site	HUS Helsinki
France	Novartis Investigative Site	Bordeaux Cedex
France	Novartis Investigative Site	Créteil
France	Novartis Investigative Site	Dijon
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Limoges cedex
France	Novartis Investigative Site	Lyon
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Poitiers
France	Novartis Investigative Site	Rennes
France	Novartis Investigative Site	Vandoeuvre les Nancy
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Frankfurt/M
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Leipzig
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Muenchen
Hong Kong	Novartis Investigative Site	Pokfulam
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Genova	GE
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Napoli
Italy	Novartis Investigative Site	Orbassano	TO
Italy	Novartis Investigative Site	Pavia	PV
Italy	Novartis Investigative Site	Pescara	PE
Italy	Novartis Investigative Site	Reggio Calabria	RC
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Italy	Novartis Investigative Site	Roma	RM
Korea, Republic of	Novartis Investigative Site	Hwasun-gun	Jeollanam-do
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Seoul	Korea
Korea, Republic of	Novartis Investigative Site	Taegu
Netherlands	Novartis Investigative Site	Amsterdam
Netherlands	Novartis Investigative Site	Rotterdam
New Zealand	Novartis Investigative Site	Grafton	Auckland
Norway	Novartis Investigative Site	Oslo
Poland	Novartis Investigative Site	Katowice
Poland	Novartis Investigative Site	Lodz
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Warszawa
Poland	Novartis Investigative Site	Wroclaw
Singapore	Novartis Investigative Site	Singapore
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Hospitalet de LLobregat	Catalunya
Sweden	Novartis Investigative Site	Göteborg
Sweden	Novartis Investigative Site	Linköping
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Uppsala
Switzerland	Novartis Investigative Site	Basel
Switzerland	Novartis Investigative Site	Genève
Taiwan	Novartis Investigative Site	Niaosong Township
United Kingdom	Novartis Investigative Site	Birmingham
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Glasgow - Scotland
United Kingdom	Novartis Investigative Site	Leeds
United Kingdom	Novartis Investigative Site	Liverpool
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Newcastle upon Tyne
United States	University of Michigan Health System Clinical Trials Office	Ann Arbor	Michigan
United States	University of Colorado Hospital	Aurora	Colorado
United States	Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. Div.of Hematologic Malignancie	Baltimore	Maryland
United States	Indiana Blood and Marrow Institute Dept of Indiana Blood&Mar (2)	Beech Grove	Indiana
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Roswell Park Cancer Institute Rosewell SC	Buffalo	New York
United States	University of Chicago Medical Center Dept. of U. of Chicago Hosp(3)	Chicago	Illinois
United States	University of Illinois at Chicago Divisionof Hematology/Oncology	Chicago	Illinois
United States	Wayne State University	Detroit	Michigan
United States	City of Hope National Medical Center	Duarte	California
United States	Duke University Medical Center	Durham	North Carolina
United States	The Jones Clinic	Germantown	Tennessee
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	MD Anderson Cancer Center/University of Texas	Houston	Texas
United States	Vanderbilt University Medical Center, Clinical Trials Center Investigational Drug Services	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Oregon Health Sciences University	Portland	Oregon
United States	Mayo Clinic - Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Swedish Cancer Institute	Seattle	Washington
United States	Stanford University Medical Center	Stanford	California
United States	H. Lee Moffitt Cancer Center & Research Institute Dept.of H. Lee Moffitt	Tampa	Florida
United States	Wake Forest University Baptist Medical Center	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Denmark,  Finland,  France,  Germany,  Hong Kong,  Italy,  Korea, Republic of,  Netherlands,  New Zealand,  Norway,  Poland,  Singapore,  Spain,  Sweden,  Switzerland,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Major Cytogenetic Response (MCyR)	Major Cytogenetic Response (MCyR) is defined as Complete Cytogenetic Response (CCyR: 0% Ph-chromosome-positive cells in metaphase in bone marrow) or Partial Cytogenetic Response (PCyR: 1-35% Ph-chromosome-positive cells in metaphase in bone marrow).	Up to End of the Treatment (Approximately 7.5 years)
Primary	Number of Participants Confirmed Overall Hematological Response (Phase II)	Hematologic response is defined as the percentage of participants in complete hematologic response (defined as the following present for at least 4 weeks: WBC count <10 x 109/L, Platelet count <450 x 109/L, Basophils <5%, No blasts and promyelocytes in peripheral blood, Myelocytes + metamyelocytes < 5% in peripheral blood, No evidence of extramedullary disease, including spleen and liver).; Hematological response was a primary outcome measure for Arm CML-AP with prior imatinib only.	Up to End of the Treatment (Approximately 7.5 years)
Secondary	Number of Participants With Overall Major Cytogenetic Responses (Phase II)	Cytogenetic responses (CyRs) in CML are based on the percentage of Ph+ metaphases in bone marrow; a value of 0% Ph+ metaphases defines a complete cytogenetic response (CCyR) and >0% to 35% defines a major cytogenetic response (MCyR). Achievement of CCyR is associated with a significant survival advantage in participants with CML-CP. MCyR was categorized as either CCyR or partial cytogenetic response (PCyR).	Up to End of the Treatment (Approximately 7.5 years)
Secondary	Number of Participants With Complete Hematologic Response (Phase II)	A Complete Hematologic Response (CHR) is obtained when all the following criteria are met: WBC = institutional ULN; platelets = 450,000/mm3; =20% basophils in peripheral blood; no blasts or promyelocytes in PB cells; < 5% myelocytes plus metamyelocytes in PB cells; no extra-medullary involvement including no hepatomegaly or splenomegaly.	Up to End of the Treatment (Approximately 7.5 years)
Secondary	Participants With (MMR) Major Molecular Response (Phase II)	MMR was defined for participants who demonstrated a reduction in BCR-ABL/control gene % transcripts to =0.1% based on international scale. The control gene used may have been either BCR or ABL.	Up to End of the Treatment (Approximately 7.5 years)
Secondary	Time to Progression (TTP) (Phase II)	Time to Progression was defined as the time from the start of nilotinib to the earliest date of Disease Progression (PD), discontinuation due to PD or death.; Disease progression was defined as an increase in the number of circulating leukemic cells via cytogenetic assessment using real-time quantitative reverse transcriptase polymerase chain reaction (PCR).	Up to End of the Treatment (Approximately 7.5 years)
Secondary	Overall Survival (OS) (Phase II)	OS was calculated for all participants as the time between the start of nilotinib and death. Participants were followed for survival after discontinuation, every 3 months, and were included in the analysis of OS. Censoring was at the date of the last contact for discontinued participants and followed up for survival.	Up to End of the Treatment (Approximately 7.5 years)
Secondary	Number of Participants With Adverse Events and Serious Adverse Events to Evaluate Long Term Safety	Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.	From First Participant First Visit to Last Participant Last Visit (Approximately 7.5 years)

External Links

•   Results for CAMN107A2101 on the Novartis Clinical Trials Website