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

• ClinicalTrials.gov Identifier: NCT00989261
• Recruitment Status: Completed
• First Posted: October 5, 2009
• Results First Posted: November 29, 2019
• Last Update Posted: December 11, 2019
• Sponsor: Daiichi Sankyo
• Information provided by (Responsible Party): Daiichi Sankyo

Tracking Information

• First Submitted Date: October 1, 2009
• First Posted Date: October 5, 2009
• Results First Submitted Date: September 25, 2019
• Results First Posted Date: November 29, 2019
• Last Update Posted Date: December 11, 2019
• Study Start Date: November 2009
• Actual Primary Completion Date: September 28, 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2019)

• Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [+] Participants) [ Time Frame: Within the first 3 cycles of treatment (84 days) ]
  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.
• Derived Disease Assessment Based on Local Morphology Including All On-Treatment Data (Safety Population, FLT3-ITD [-] Participants) [ Time Frame: Within the first 3 cycles of treatment (84 days) ]
  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.
• Number of Participants With Composite Complete Remission (CRc), Categorised by FLT3-ITD Status [ Time Frame: within 28 months ]
  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.

• Original Primary Outcome Measures (submitted: October 1, 2009): Overall complete remission rate and complete remission rate [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]

Current Secondary Outcome Measures (submitted: November 11, 2019)

• Duration of Composite Complete Remission in FLT3-ITD (+) Participants Who Achieved CRc Based on All On-Treatment Data [ Time Frame: From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment ]
  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.
• Duration of Composite Complete Remission in FLT3-ITD (-) Participants Who Achieved CRc Based on All On-Treatment Data [ Time Frame: From time at which CRc was achieved until disease progression or death, up to approximately 3 years post treatment ]
  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.
• Duration of Any Response in FLT3-ITD (+) Participants [ Time Frame: From the time of any response until disease progression or death, up to approximately 3 years post treatment ]
  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).
• Duration of Any Response in FLT3-ITD (-) Participants [ Time Frame: From the time of any response until disease progression or death, up to approximately 3 years post treatment ]
  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).
• Median Duration of Leukemia-free Survival in FLT3-ITD (+) Participants [ Time Frame: From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment ]
  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).
• Median Duration of Leukemia-free Survival in FLT3-ITD (-) Participants [ Time Frame: From the time CRc was achieved until disease progression or death, up to approximately 3 years post treatment ]
  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).
• Median Duration of Overall Survival in FLT3-ITD (+) Participants [ Time Frame: Time from first dose to death from any cause, up to 3 years post treatment ]
  Kaplan-Meier analysis of overall survival (Safety Population)
• Median Duration of Overall Survival in FLT3-ITD (-) Participants [ Time Frame: Time from first dose to death from any cause, up to approximately 3 years post treatment ]
  Kaplan-Meier analysis of overall survival (Safety Population)
• Early Treatment-related Death [ Time Frame: Within first 3 cycles of treatment (84 days) ]
  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.

Original Secondary Outcome Measures (submitted: October 1, 2009)

• Duration of remission [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Remission rates for all categories of remission [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Disease-free survival [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Overall survival [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Treatment induction and post induction treatment-related mortality [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Safety and tolerability of AC220 as determined by adverse event reporting, clinical laboratory results, vital signs, physical exams, and electrocardiograms (ECG). [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Pharmacokinetic analysis of AC220. Analysis of phosph-FLT3 and other pharmacodynamic markers. [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Impact of AC220 on hematological improvement, bridge to transplant, duration of leukemia control, blood and platelet transfusions, infections, days of hospitalization, performance status [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]
• Pharmacogenetic analyses, correlation of remission with FLT3-ITD allelic ratio and other parameters using other assays. [ Time Frame: Interim analysis following recruitment of 60 patients. Final analysis following study completion. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy Study for AC220 to Treat Acute Myeloid Leukemia (AML)
• 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
• Brief 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Acute Myeloid Leukemia

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.

Other Name: AC010220 × 2HCl, oral powder for reconstitution

Study Arms

• Experimental: Cohort 1; ≥60 years of age

  Participants ≥60 years of age who were relapsed after one first-line chemotherapy regimen (with or without consolidation) and after first complete remission <12 months or are primary refractory to first-line chemotherapy received a starting dose of 200 mg/day quizartinib.

  Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-)

  After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.

  Intervention: Drug: Compound AC220
• Experimental: Cohort 2; ≥18 years of age

  Participants ≥18 years of age (including participants ≥60 years of age) who were relapsed or refractory after one second-line (salvage) regimen or after hematopoietic stem cell transplant (HSCT) received a starting dose of 200 mg/day quizartinib.

  Exploratory: FLT3-ITD (+) and FLT3-ITD (-) Confirmatory: FLT3-ITD (+) and FLT3-ITD (-)

  After an amendment, male participants received a starting dose of 135 mg/day quizartinib and all females received a starting dose of 90 mg/day.

  Intervention: Drug: Compound AC220

• Publications *: Cortes J, Perl AE, Dohner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Kramer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, Levis M. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018 Jul;19(7):889-903. doi: 10.1016/S1470-2045(18)30240-7. Epub 2018 May 31.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 18, 2017): 333
• Original Estimated Enrollment (submitted: October 1, 2009): 180
• Actual Study Completion Date: December 31, 2014
• Actual Primary Completion Date: September 28, 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 β-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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, France, Germany, Italy, Netherlands, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT00989261
• Other Study ID Numbers: AC220-002; 2009-013093-41 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• URL: https://vivli.org/ourmember/daiichi-sankyo/

• Current Responsible Party: Daiichi Sankyo
• Original Responsible Party: Robert Corringham, MD / Sr. VP, Clinical Develoment, Ambit Biosciences Corporation
• Current Study Sponsor: Daiichi Sankyo
• Original Study Sponsor: Ambit Biosciences Corporation
• Collaborators: Not Provided

Investigators

• Study Director: Interim Chief Medical Officer; Ambit Biosciences Corporation

• PRS Account: Daiichi Sankyo
• Verification Date: December 2019