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Trial record 7 of 42 for:    Recruiting, Not yet recruiting, Enrolling by invitation Studies | Astellas [Lead]

A Study of ASP2215 Versus Salvage Chemotherapy In Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation

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ClinicalTrials.gov Identifier: NCT03182244
Recruitment Status : Recruiting
First Posted : June 9, 2017
Last Update Posted : October 5, 2018
Sponsor:
Information provided by (Responsible Party):
Astellas Pharma Inc

Brief Summary:
The purpose of this study is to determine the clinical benefit of ASP2215 therapy in participants with FMS-like tyrosine kinase (FLT3) mutated AML who are refractory to or have relapsed after first-line AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. In addition, this study will evaluate safety as well as determine the overall efficacy in event-free survival (EFS) and complete remission (CR) rate of ASP2215 compared to salvage chemotherapy.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia With FMS-like Tyrosine Kinase (FLT3) Mutation Drug: gilteritinib Drug: LoDAC (Low Dose Cytarabine) Drug: MEC (Mitoxantrone, Etoposide, Cytarabine) Drug: FLAG (Granulocyte colony-stimulating factor (G-CSF), Fludarabine, Cytarabine) Phase 3

Detailed Description:

Participants considered an adult according to local regulations at the time of signing informed consent will be randomized in a 1:1 ratio to receive ASP2215 or salvage chemotherapy. Participants will enter the screening period up to 14 days prior to the start of treatment. Prior to randomization, the investigator will preselect a salvage chemotherapy regimen for each participant; options will include low-dose cytarabine (LoDAC), mitoxantrone, etoposide and intermediate-dose cytarabine (MEC) or fludarabine, high-dose cytarabine and granulocyte colony-stimulating factor (FLAG). The randomization will be stratified by response to first-line therapy and preselected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles.

Among the participants, approximately 20 Chinese participants who are randomized into the ASP2215 arm will be allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort will be requested to be hospitalized from the date of randomization (Day 1) to at least the completion of all the assessments planned on Day 2. All participants in the PK cohort will undergo blood sampling for PK measurement of ASP2215. Participants in PK cohort will be administered the study drug in the same manner and undergo the same efficacy and safety assessments as other participants except for blood sampling for additional PK measurements.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 318 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 3 Open-label, Multicenter, Randomized Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FLT3 Mutation
Actual Study Start Date : January 15, 2018
Estimated Primary Completion Date : March 2020
Estimated Study Completion Date : June 2020


Arm Intervention/treatment
Experimental: ASP2215
ASP2215 will be administered orally once daily.
Drug: gilteritinib
oral
Other Name: ASP2215

Active Comparator: Salvage chemotherapy
Options for salvage chemotherapy are limited to the following: Low-dose Cytarabine (LoDAC) will be administered twice daily by subcutaneous or intravenous injection for 10 days. Mitoxantrone, Etoposide, Cytarabine (MEC Induction Chemotherapy) will each be administered intravenously for 5 days (days 1 through 5). Granulocyte colony-stimulating factor (G-CSF) will be administered intravenously for 5 days (days 1 through 5) and also recommended 7 days after completing chemotherapy, Fludarabine and Cytarabine administered intravenously for 5 days (days 2 through 6) (FLAG Induction Chemotherapy).
Drug: LoDAC (Low Dose Cytarabine)
subcutaneous (SC) or intravenous (IV) injection

Drug: MEC (Mitoxantrone, Etoposide, Cytarabine)
intravenous

Drug: FLAG (Granulocyte colony-stimulating factor (G-CSF), Fludarabine, Cytarabine)
intravenous

Experimental: ASP2215 PK in Chinese population
PK samples will be collected after single and multiple doses in Chinese subjects.
Drug: gilteritinib
oral
Other Name: ASP2215




Primary Outcome Measures :
  1. Overall survival [ Time Frame: up to 3 years ]
    Overall survival (OS) is defined as the time from the date of randomization until the date of death from any cause. For a participant who is not known to have died by the end of study follow-up, OS is censored at the date of last contact.


Secondary Outcome Measures :
  1. Event-free survival [ Time Frame: up to 3 years ]
    Event-free survival (EFS) is defined as the time from the date of randomization until the date of documented relapse (including relapse after complete remission (CR), complete remission with incomplete platelet recovery (CRp) and complete remission with incomplete hematologic recovery (CRi)), treatment failure or death whichever occurs first.

  2. Complete remission [ Time Frame: up to 3 years ]
    For participants to be classified as being in CR, the participants must have bone marrow regenerating normal hematopoietic cells and achieve a morphologic leukemia-free state and must have an absolute neutrophil count (ANC) greater than 1 x 10^9/L and platelet count ≥ 100 x 10^9/L and normal marrow differential with less than 5% blasts, and will be red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). There should be no evidence of extramedullary leukemia.

  3. Leukemia-free survival [ Time Frame: up to 3 years ]
    Leukemia-free survival (LFS) is defined as the time from the date of first composite complete remission (CRc) until the date of documented relapse or death for participants who achieve CRc. For a participant who is not known to have relapsed or died, LFS is censored on the date of last relapse-free disease assessment date.

  4. Duration of composite complete remission (CRc) [ Time Frame: up to 3 years ]
    Duration of CRc is defined as the time from the date of first CRc until the date of documented relapse for participants who achieve CRc.

  5. Duration of complete remission (CR) [ Time Frame: up to 3 years ]
    Duration of CR is defined as the time from the date of first CR until the date of documented relapse for participants who achieve CR.

  6. Duration of complete remission with incomplete platelet recovery (CRp) [ Time Frame: up to 3 years ]
    Duration of CRp is defined as the time from the date of first CRp until the date of documented relapse for participants who achieve CRp.

  7. Duration of complete remission with incomplete hematologic recovery (CRi) [ Time Frame: up to 3 years ]
    Duration of CRi is defined as the time from the date of first CRi until the date of documented relapse for participants who achieve CRi.

  8. Composite complete remission rate [ Time Frame: up to 3 years ]
    CRc rate is defined as the remission rate of all CR, CRp and CRi (i.e., CR + CRp + CRi)

  9. Transplantation rate [ Time Frame: up to 3 years ]
    Transplantation rate is defined as the percentage of participants undergoing hematopoietic stem cell transplant (HSCT).

  10. Brief Fatigue Inventory [ Time Frame: up to 3 years ]
    Brief Fatigue Inventory (BFI) will assess the severity of fatigue and the impact of fatigue on daily functioning in participants with fatigue due to cancer and cancer treatment. The BFI short form has 9 items and a 24-hour recall. A global fatigue score is computed by averaging the 9 items.

  11. Safety assessed by adverse events [ Time Frame: up to 3 years ]
    An adverse event (AE) is defined as any untoward medical occurrence in a participant administered a study drug or has undergone study procedures and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unintended sign (including an abnormal laboratory finding), symptom or disease temporally associated with the use of a medicinal investigational) product, whether or not related to the medicinal (investigational) product.

  12. Safety assessed by laboratory test: chemistry [ Time Frame: up to 3 years ]
    To assess chemistry as a criteria of safety variables

  13. Safety assessed by laboratory test: hematology [ Time Frame: up to 3 years ]
    To assess hematology as a criteria of safety variables

  14. Safety assessed by laboratory test: coagulation [ Time Frame: up to 3 years ]
    To assess coagulation as a criteria of safety variables

  15. Safety assessed by laboratory test: urinalysis [ Time Frame: up to 3 years ]
    To assess urinalysis as a criteria of safety variable

  16. Number of participants with vital signs abnormalities and/or adverse events [ Time Frame: up to 3 years ]
    Number of participants with potentially clinically significant vital sign values

  17. Safety assessed by electrocardiograms [ Time Frame: up to 3 years ]
    Electrocardiograms (ECGs) will be obtained after the participant has rested quietly and is awake in a fully supine position (or semi-recumbent, if supine not tolerated) for 10 minutes before the first ECG from a triplicate.

  18. Pharmacokinetics (PK) of ASP2215: Area under the concentration curve at 24 hours (AUC24) [ Time Frame: Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 15: predose and up to 24 hours post-dose. A cycle is 28 days. ]
    AUC24 will be derived from the PK blood samples collected.

  19. PK of ASP2215: Maximum concentration (Cmax) [ Time Frame: Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 15: predose and up to 24 hours post-dose. A cycle is 28 days. ]
    Cmax will be derived from the PK blood samples collected.

  20. PK of ASP2215: Observed trough concentration (Ctrough) [ Time Frame: Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 8: predose; Cycle 1 Day 15: predose and up to 24 hours post-dose; Day 1 predose of each subsequent cycle. A cycle is 28 days. ]
    Ctrough will be derived from the PK blood samples collected.

  21. PK of ASP2215: Time after dosing when Cmax occurs (tmax) [ Time Frame: Cycle 1 Day 1: predose and up to 24 hours post-dose; Cycle 1 Day 15: predose and up to 24 hours post-dose. A cycle is 28 days. ]
    tmax will be derived from the PK blood samples collected.

  22. ASP2215 concentration in blood [ Time Frame: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 1 Day 15: predose; Day 1 predose of each subsequent cycle. A cycle is 28 days. ]
    Blood samples will be taken to measure the concentration of the drug

  23. Safety assessed by Eastern Cooperative Oncology Group (ECOG) performance scores [ Time Frame: up to 3 years ]
    ECOG performance status measured on 6 point scale to assess participant's performance status. 0=Fully active, able to carry on all pre-disease activities without restriction; 1=Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature; 2= Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours; 3=Capable of only limited self-care, confined to bed or chair more than 50% of waking hours; 4=Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; 5=Dead. 0=Best status; 5=Worst status.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject has a diagnosis of primary AML or AML secondary to myelodysplastic syndrome (MDS) according to World Health Organization (WHO) classification as determined by pathology review at the treating institution.
  • Subject is refractory to or relapsed after first-line AML therapy (with or without HSCT)

    • Refractory to first-line AML therapy is defined as:

      a. Subject did not achieve CR/CRi/CRp under initial therapy. A subject eligible for standard therapy must receive at least 1 cycle of an anthracycline containing induction block in standard dose for the selected induction regimen. A subject not eligible for standard therapy must have received at least 1 complete block of induction therapy seen as the optimum choice of therapy to induce remission for this subject.

    • Untreated first hematologic relapse is defined as:

      1. Subject must have achieved a CR/CRi/CRp with first-line treatment and has hematologic relapse.
  • Subject is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A subject with rapidly proliferative disease and unable to wait for the central lab results can be enrolled based on a local test performed after completion of the last interventional treatment. Subjects can be enrolled from a local test result if the subjects have any of the following FLT3 mutations: FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD)/D835 or FLT3-TKD/I836.
  • Subject has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
  • Subject is eligible for preselected salvage chemotherapy.
  • Subject must meet the following criteria as indicated on the clinical laboratory tests:

    • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x upper limit of normal (ULN)
    • Serum total bilirubin (TBL) ≤ 1.5 x ULN
    • Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation.
  • Subject is suitable for oral administration of study drug.
  • Subject agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

  • Subject was diagnosed as acute promyelocytic leukemia.
  • Subject has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
  • Subject has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
  • Subject is in second or later hematologic relapse or has received salvage therapy for refractory disease.
  • Subject has clinically active central nervous system leukemia..
  • Subject has been diagnosed with another malignancy, unless disease-free for at least 5 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Subjects with organ-confined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
  • Subject has received prior treatment with ASP2215 or other FLT3 inhibitors (with the exception of sorafenib and midostaurin used in first-line therapy regimen as part of induction, consolidation and/or maintenance).
  • Subject has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation.
  • Subject has had major surgery within 4 weeks prior to the first study dose.
  • Subject has radiation therapy within 4 weeks prior to the first study dose.
  • Subject has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or subject with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram (ECHO) performed within 1 month prior to study entry results in a left ventricular ejection fraction (LVEF) that is ≥ 45%.
  • Subject with mean of triplicate Fridericia-corrected QT interval (QTcF) > 450 ms at Screening based on central reading.
  • Subject with Long QT Syndrome at Screening.
  • Subject with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal [LLN]).
  • Subject requires treatment with concomitant drugs that are strong inducers of CYP3A.
  • Subject requires treatment with concomitant drugs that are strong inhibitors or inducers of P-gp with the exception of drugs that are considered absolutely essential for the care of the subject.
  • Subject requires treatment with concomitant drugs that target serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine receptor 2B (5HT2BR) receptors or sigma nonspecific receptor with the exception of drugs that are considered absolutely essential for the care of the subject.
  • Subject has an active uncontrolled infection.
  • Subject is known to have human immunodeficiency virus infection.
  • Subject has active hepatitis B or C or other active hepatic disorder.
  • Subject has any condition which makes the subject unsuitable for study participation.
  • Subject has active clinically significant (graft-versus-host disease) GVHD or is on treatment with systemic corticosteroids for GVHD.
  • Subject has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03182244


Contacts
Contact: Astellas Pharma, Inc. +81-3-3244-0512 Astellas.registration@astellas.com

  Show 45 Study Locations
Sponsors and Collaborators
Astellas Pharma Inc
Investigators
Study Director: Medical Director Astellas Pharma Inc

Responsible Party: Astellas Pharma Inc
ClinicalTrials.gov Identifier: NCT03182244     History of Changes
Other Study ID Numbers: 2215-CL-0303
First Posted: June 9, 2017    Key Record Dates
Last Update Posted: October 5, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Astellas Pharma Inc:
gilteritinib
Acute Myeloid Leukemia (AML)
ASP2215

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Fludarabine
Fludarabine phosphate
Etoposide phosphate
Etoposide
Cytarabine
Mitoxantrone
Lenograstim
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Phytogenic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Antiviral Agents
Anti-Infective Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Adjuvants, Immunologic