Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)

Acute Myeloid Leukemia Clinical Trial

— ACE  

Official title:

Phase 2 Open-Label, AC220 Monotherapy Efficacy (ACE) Study in Patients With Acute Myeloid Leukemia (AML) With and Without FLT3-ITD Activating Mutations

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00989261
• Other study ID #: AC220-002
• Secondary ID: 2009-013093-41
• Status: Completed
• Phase: Phase 2
• Start date: November 2009
• Est. completion date: December 31, 2014

Study information

• Verified date: December 2019
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

AC220 will be administered as a once daily oral solution given continuously as 28-day treatment cycles, without any rest periods, until disease progression, relapse, intolerance to the drug, or elective allogeneic hematopoietic stem cell transplantation (HSCT).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 333
• Est. completion date: December 31, 2014
• Est. primary completion date: September 28, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

Current enrollment is open only to FLT3-ITD positive, Cohort 1.

Inclusion Criteria:

1. Males and females age =18 years in second relapse or refractory.

2. Males and females age =60 years in first relapse or refractory.

3. Must have baseline bone marrow sample taken.

4. Morphologically documented primary AML or AML secondary to myelodysplastic syndrome (MDS with =20% bone marrow or peripheral blasts), as defined by the World Health Organization (WHO) criteria, confirmed by pathology review at treating institution.

5. Able to swallow the liquid study drug.

6. Eastern Cooperative Oncology Group performance status of 0 to 2

7. In the absence of rapidly progressing disease, the interval from prior treatment to time of AC220 administration will be at least 2 weeks for cytotoxic agents or at least 5 half-lives for noncytotoxic agents. The use of chemotherapeutic or antileukemic agents other than hydroxyurea is not permitted during the study with the possible exception of intrathecal (IT) therapy at the discretion of the Investigator and with the agreement of the Sponsor.

8. Persistent chronic clinically significant non-hematological toxicities from prior treatment must be =Grade 1.

9. Prior therapy with FLT3 inhibitors is permitted, except previous treatment with AC220.

10. Serum creatinine =1.5 × upper limit of normal (ULN) and glomerular filtration rate (GFR) > 30 mL/min

11. Serum potassium, magnesium, and calcium levels should be at least within institutional normal limits.

12. Total serum bilirubin =1.5 × ULN

13. Serum aspartate transaminase (AST) and/or alanine transaminase (ALT) =2.5 × ULN

14. Females of childbearing potential must have a negative pregnancy test (urine ß-hCG).

15. Females of childbearing potential and sexually mature males must agree to use a medically accepted method of contraception throughout the study.

16. Written informed consent must be provided.

Exclusion Criteria:

1. Patients over the age of 85 years except at the discretion of the Investigator and with agreement of the Sponsor.

2. Diagnosis of acute promyelocytic leukemia

3. Diagnosis of chronic myelogenous leukemia (CML) in blast crisis

4. AML in relapse or refractory after 3 or more previous lines of chemotherapy (and/or HSCT) treatment

5. AML or antecedent MDS secondary to prior chemotherapy

6. Persistent clinically significant non-hematological toxicity that is Grade >1 by NCI CTCAE v4 from prior chemotherapy

7. Patients who have had HSCT and are within 100 days of transplant and/or are still taking immunosuppressive drugs and/or have clinically significant graft-versus-host disease requiring treatment and/or have >Grade 1 persistent non hematological toxicity related to the transplant

8. Clinically active central nervous system (CNS) leukemia. Patients with CNS leukemia, which is controlled, but who are still receiving IT therapy at study entry may be considered eligible and continue receive IT therapy at the discretion of the Investigator and with agreement of the Sponsor.

9. Patients who have previously received AC220

10. Disseminated intravascular coagulation (DIC) (diagnosis by laboratory or clinical assessment)

11. Major surgery within 4 weeks prior to enrollment in the study

12. Radiation therapy within 4 weeks prior to, or concurrent with study

13. Use of concomitant drugs that prolong the time between the start of the Q wave and the end of the T wave (QT)/corrected interval between the Q wave and T wave (QTc) interval and/or are CYP3A4 inhibitors are prohibited with the exception of antibiotics, antifungals, and other antimicrobials that are used as standard of care to prevent or treat infections and other such drugs that are considered absolutely essential for the care of the patient.

14. Uncontrolled or significant cardiovascular disease

15. Women who are pregnant, lactating, or unwilling to use contraception if of childbearing potential

16. Men who are unwilling to use contraception if their partners are of childbearing potential

17. Active, uncontrolled infection

18. Human immunodeficiency virus positivity

19. Active hepatitis B or C or other active liver disease

20. History of cancer, except Stage 1 cervix or nonmelanotic skin cancer, with the possible exception of patients in complete remission

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Compound AC220
Precomplexed powder in bottle formulation supplied as 200 mg in a 60 cc polyethylene terephthalate (PET) plastic bottle. Requires reconstitution by a pharmacist, must be stored securely, and protected from light.

Locations

Country	Name	City	State
Canada	Princess Margaret Hospital	Toronto	Ontario
France	Hopital Avicenne	Bobigny
France	Centre Hospitalier Universitaire d'Angers	d'Angers
France	Centre Hospitalier Universitaire Grenoble	Grenoble
France	Centre Hospitalier de Versailles	Le Chesnay
France	Hopital Claude Huriez	Lille
France	Centre Hospitalier Universitaire Limoges	Limoges
France	Hopital Edouard Herriot	Lyon
France	Institut Paoli Calmettes Centre Regional de Lutte Contre le Cancer	Marseille	Cedex 9
France	Hopital Saint-Antoine	Paris
France	Hopital Saint-Louis	Paris
France	Hopital Haut-Leveque	Pessac
France	Centre Henry Becquerel, Service d'Hematologie	Rouen
France	Centre Hospitalier Regional Universitaire, Hopital de Hautepierre	Strasbourg
France	Hematologie - CHU Purpan	Toulouse	Cedex
France	Centre Hospitalier Universitaire Brabois	Vandoeuvre les Nancy
Germany	Charite Campus Virchow Klinikum	Berlin
Germany	Charite, Campus Benjamin Franklin	Berlin
Germany	Universitatsklinikum Bonn	Bonn
Germany	Unikliniksklinikum Carl Gustav Carus	Dresden
Germany	Uniklinik Essen, Westdeutsches Tumorzentrum	Essen
Germany	Klinikum der Johann Wolfgang Goethe Universitat	Frankfurt am Main
Germany	Asklepios Klinik St Georg	Hamburg
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Universitatsklinikum Heidelberg	Heidelberg
Germany	Universitatsklinikum Jena	Jena
Germany	Universitatsklinikum Leipzig Selbstandige Abteilung fur Hamatologie	Leipzig
Germany	Universitatsklinikum Magdeburg	Magdeburg
Germany	Universitatsklinikum Mannheim	Mannheim
Germany	Philipps-Universitat Marburg	Marburg
Germany	Klinikum rechts der Isar, Technische Universitat Munchen	Munchen
Germany	Universitatsklinikum Munster	Munster
Germany	Universitatsklinikum Regensburg Abteilung fur Hamatologie	Regensburg
Germany	Robert-Bosch-Krankenhaus GmbH	Stuttgart
Germany	Universitatsklinikum Tubingen	Tubingen
Germany	Universitatsklinikum Ulm	Ulm
Germany	Universitatsklinikum Wurzburg	Wurzburg
Italy	Instituto Di Ematologia "L.Ea. Seragnoli"	Bologna
Italy	Unita Trapianti di Midollo Osseo per Adulti	Brescia
Italy	Presidio Ospedaliero "A. Businco" - Centro di Riferimento Oncologico Regionale	Cagliari
Italy	Azienda Ospedaliera-Universitaria Vittorio Emanuele-Ferrarotto	Catania
Italy	Azienda Ospedaliera Universitaria San Martino	Genova
Italy	Farmacia Ospidaliera	Orbassano
Italy	Ospedale Civile S. Maria delle Croci	Ravenna
Italy	Ospedale Sant Eugenio	Roma
Italy	Universita Degli Studi di Roma Tor Vergata	Roma
Italy	Azienda Ospedaliero Universitaria Senese	Siena
Italy	Azienda Ospedaliero Universitaria S. Maria della Misericordia di Udine, Clinica Ematologica	Udine
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Utrecht University Medical Centre, Dept. of Hematology	Utrecht
Poland	Dolnoslaskie Centrum Transplantacji Komorkowych z	Wroclaw
Spain	Hospital Clinic i Provincial de Barcelona	Barcelona
Spain	Hospital de la Santa Creu i Sant Pau	Barcelona
Spain	Institut Catala d'Oncologia del Hospital Universitari Germans	Barcelona
Spain	Instituto Catalan de Oncologia-Hospital Universitari de Girona	Girona
Spain	Hospital de la Princesa, Servicio de Hematologia	Madrid
Spain	Hospital General Universitario Gregorio Maranon	Madrid
Spain	Clinica Universidad de Navarra	Pamplona	Navarra
Spain	Hospital Universitario de Salamanca, Hospital Clinico, Servicio de Hematologia	Salamanca
Spain	Hospital La Fe, Servicio de Hematologia	Valencia
United Kingdom	Addenbrook's Hospital	Cambridge
United Kingdom	Castle Hill Hospital	Cottingham
United Kingdom	Saint James University Hospital, Institute of Oncology	Leeds
United Kingdom	Hanmmersmith Hospital, Dept. of Hematology	London
United Kingdom	Nottingham University Hospitals NHS Trust	Nottingham
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Maryland	Baltimore	Maryland
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Karmanos Cancer Institute	Detroit	Michigan
United States	Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	M.D. Anderson Cancer Center	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	University of Wisconsin Hospital and Clinics	Madison	Wisconsin
United States	Clinical Trials Center	Nashville	Tennessee
United States	The Vanderbuilt Clinic	Nashville	Tennessee
United States	Columbia University	New York	New York
United States	Abramson Cancer Center	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California, San Francisco	San Francisco	California
United States	Seattle Cancer Care Alliance	Seattle	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Canada,  France,  Germany,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants)	Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD[+] Participants); Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 x 10^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.	Within the first 3 cycles of treatment (84 days)
Primary	Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants)	Derived disease assessment based on local morphology of bone marrow disease performed by each local site pathologist, including all on-treatment data (Safety Population, FLT3-ITD[-] Participants); Modified from Cheson et al, abbreviations include the following: CR=complete remission; CRc=composite complete remission (CR+CRp+CRi); CRi=complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia=all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 x 10^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib=All criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion; CRp=complete remission with incomplete platelet recovery; NR=no response; PR=partial remission.	Within the first 3 cycles of treatment (84 days)
Primary	Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status	CRc is defined as composite complete remission (CR+CRp+CRi) - CR = complete remission; CRp = complete remission with incomplete platelet recovery; CRi = complete remission with incomplete hematological recovery, includes participants who met CRia criteria plus participants who met CRib criteria; CRia = all criteria specified for CR are met except for incomplete hematological recovery with residual neutropenia <1 x 10^9/L with or without complete platelet recovery. Red blood cell and platelet transfusion independence is not required; CRib = all criteria for CR or CRp are met, except for recent red blood cell or platelet transfusion.	within 28 months
Secondary	Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data	Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population).; The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of >1%.Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Secondary	Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data	Kaplan-Meier analysis of duration of composite complete remission derived based on local morphology including all on-treatment data (Safety Population).; The definition of relapse at CRc includes an evaluation of blasts in the peripheral blood of >1%.Though not specified in the protocol, the addition of these criteria was deemed necessary for consistency with the Cheson criteria.	From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Secondary	Duration of Any Response in FLT3-ITD (+) Participants	Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for participants who achieved a response during the first 3 cycles of treatment (Safety Population).	From the time of any response until disease progression or death, up to approximately 3 years post treatment
Secondary	Duration of Any Response in FLT3-ITD (-) Participants	Kaplan-Meier analysis of duration of any response (CR, CRp, CRi, or PR), derived based on local morphology for participants who achieved a response during the first 3 cycles of treatment (Safety Population).	From the time of any response until disease progression or death, up to approximately 3 years post treatment
Secondary	Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants	Kaplan-Meier analysis of leukemia-free survival in participants who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population).	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Secondary	Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants	Kaplan-Meier analysis of leukemia-free survival in participants who achieved a CRc in the first three cycles of treatment derived based on local morphology (Safety Population).	From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment
Secondary	Median Duration of Overall Survival in FLT3-ITD (+) Participants	Kaplan-Meier analysis of overall survival (Safety Population)	Time from first dose to death from any cause, up to 3 years post treatment
Secondary	Median Duration of Overall Survival in FLT3-ITD (-) Participants	Kaplan-Meier analysis of overall survival (Safety Population)	Time from first dose to death from any cause, up to approximately 3 years post treatment
Secondary	Early Treatment-related Death	Early treatment-related deaths included all treatment-related deaths prior to the end of Cycle 3 with a 3-day window (Cycle 3 end date + 3 days), unless the death was following a CRc response assessed by the Investigator.	Within first 3 cycles of treatment (84 days)