Clinical trial NCT03182244: A Study of ASP2215 Versus Salvage Chemotherapy In Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase 3 (FLT3) Mutation
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: AML With FLT3 Mutation
Keywords: gilteritinib
Acute Myeloid Leukemia (AML)
ASP2215
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2017-06-09
Enrollment: 276
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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

Among the participants, approximately 20 Chinese participants who were randomized into the ASP2215 arm were allocated to the pharmacokinetic (PK) cohort. Participants in the PK cohort were 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 underwent blood sampling for PK measurement of ASP2215. Participants in PK cohort were administered the study drug in the same manner and underwent the same efficacy and safety assessments as other participants except for blood sampling for additional PK measurements.

Eligibility criteria: Inclusion Criteria:

* Participant 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.
* Participant is refractory to or relapsed after first-line AML therapy (with or without HSCT)

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

    a. Participant did not achieve CR/CRi/CRp under initial therapy. A participant 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 participant 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 participant.
  * Untreated first hematologic relapse is defined as:

    1. Participant must have achieved a CR/CRi/CRp with first-line treatment and has hematologic relapse.
* Participant is positive for FLT3 mutation in bone marrow or whole blood as determined by the central lab. A participant 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. Participants can be enrolled from a local test result if the participants have any of the following FLT3 mutations: FLT3-internal tandem duplication (ITD), FLT3-tyrosine kinase domain (TKD)/D835 or FLT3-TKD/I836.
* Participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
* Participant is eligible for preselected salvage chemotherapy.
* Participant 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.
* Participant is suitable for oral administration of study drug.
* Participant agrees not to participate in another interventional study while on treatment.

Inclusion Criteria for COE:

Participant is eligible for the COE if they continue to meet all inclusion criteria from the main protocol in addition to the following when the participant is evaluated for eligibility to participate in the COE portion of the study:

* Participant has received study treatment of either LoDAC, MEC or FLAG and has no response or progressive disease.
* Participant have not received other antileukemic therapy after EOT (hydroxyurea is allowed for the control of peripheral leukemic blasts in participants with leukocytosis).
* Participant agrees not to participate in another interventional study while on treatment.

Exclusion Criteria:

* Participant was diagnosed as acute promyelocytic leukemia.
* Participant has BCR-ABL-positive leukemia (chronic myelogenous leukemia in blast crisis).
* Participant has AML secondary to prior chemotherapy for other neoplasms (except for MDS).
* Participant is in second or later hematologic relapse or has received salvage therapy for refractory disease.
* Participant has clinically active central nervous system leukemia..
* Participant has been diagnosed with another malignancy, unless disease-free for at least 5 years. Participants 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. Participants 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.
* Participant 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).
* Participant has clinically significant abnormality of coagulation profile, such as disseminated intravascular coagulation.
* Participant has had major surgery within 4 weeks prior to the first study dose.
* Participant has radiation therapy within 4 weeks prior to the first study dose.
* Participant has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or participant 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%.
* Participant with mean of triplicate Fridericia-corrected QT interval (QTcF) \> 450 ms at Screening based on central reading.
* Participant with Long QT Syndrome at Screening.
* Participant with hypokalemia and hypomagnesemia at Screening (defined as values below lower limit of normal \[LLN\]).
* Participant requires treatment with concomitant drugs that are strong inducers of CYP3A.
* Participant 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 participant.
* Participant 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 participant.
* Participant has an active uncontrolled infection.
* Participant is known to have human immunodeficiency virus infection.
* Participant has active hepatitis B or C or other active hepatic disorder.
* Participant has any condition which makes the participant unsuitable for study participation.
* Participant has active clinically significant (graft-versus-host disease) GVHD or is on treatment with systemic corticosteroids for GVHD.
* Participant has an FLT3 mutation other than the following: FLT3-ITD, FLT3-TKD/D835 or FLT3-TKD/I836.

Exclusion Criteria for COE:

Participant will be excluded from participation in the COE if they meet any of the exclusion criteria listed in the main protocol or when the participant is evaluated for eligibility to participate in the COE portion of the study.

Primary outcomes:
measure: Overall Survival (OS)
timeFrame: From the date of randomization up to the date of death (up to approximatley 74 months)
Secondary outcomes:
measure: Event-Free Survival (EFS)
timeFrame: From the date of randomization up to the date of documented relapse, treatment failure or death from any cause, off-treatment relapse and start of new AML therapy (up to approximately 74 months)
measure: Complete Remission (CR) Rate
timeFrame: From the date of randomization up to approximately 74 months
measure: Duration of CR
timeFrame: From date of achieving CR until date of confirmed relapse (maximum duration was 53.4 months )
measure: Duration of Composite Complete Remission (CRc)
timeFrame: From date of achieving CRc until date of confirmed relapse (maximum duration was 60 months)
measure: Duration of CR/Complete Remission With Partial Hematologic Recovery (CRh)
timeFrame: From date of achieving CR/CRh until date of confirmed relapse (maximum duration was 58.1 months)
measure: Duration Of Response (DOR)
timeFrame: From date of achieving CRc/PR until date of confirmed relapse (maximum duration was 52.1 months)
measure: CR/CRh Rate
timeFrame: From the date of randomization up to approximately 74 months
measure: Best Response Rate
timeFrame: From the date of randomization up to approximately 74 months
measure: Leukemia-Fee Survival (LFS)
timeFrame: From first day of achieving first CRc to the first day of confirmed relapse/death (maximum duration was 60.0 months)
measure: Composite Complete Remission (CRc)
timeFrame: From the date of randomization up to approximately 74 months
measure: Time to CRc
timeFrame: From randomization until date of first CRc (up to approximately 74 months)
measure: Time to CR
timeFrame: From randomization until date of first CR (up to approximately 74 months)
measure: Time to Response
timeFrame: From randomization until date of first CRc or PR (up to approximately 74 months)
measure: Time to CR/CRh
timeFrame: From randomization until date of first CR/CRh (up to approximately 74 months)
measure: Percentage of Participants With Transfusion Conversion and Transfusion Maintenance
timeFrame: Baseline up to approximately 74 months
measure: Percentage of Participants With Transplantation Rate
timeFrame: Baseline up to approximately 74 months
measure: Change From Baseline in Brief Fatigue Inventory (BFI)
timeFrame: Baseline, End of treatment (63 months)
measure: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From the date of first dose up to approximately 74 months
measure: Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Scores
timeFrame: Baseline, end of treatment visit (63 months)
measure: Pharmacokinetics (PK) of Gilteritinib in Chinese PK Cohort: Area Under the Concentration Curve at 24 Hours (AUC24)
timeFrame: Cycle 1 Day 1(C1D1): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, Cycle 1 Day 15(C1D15): predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose
measure: PK of Gilteritinib in Chinese PK Cohort: Maximum Concentration (Cmax)
timeFrame: C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hour post dose
measure: PK of Gilteritinib: Observed Trough Concentration (Ctrough)
timeFrame: Predose on C1D15
measure: PK of Gilteritinib in Chinese PK Cohort: Time to Maximum Concentration (Tmax)
timeFrame: C1D1: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose, C1D15: predose, 0.5, 1, 2, 3, 4, 6, 10, 24 hours (+/- 20 minutes) post dose
measure: Ctrough Concentration of Gilteritinib
timeFrame: Predose C1D8, C1D15, Day 1 of each cycle from C2 to C65, C67D1,C68D1,C69D1,C70D1
Other outcomes:
Locations:
city: Beijing
country: China
facility: Site CN103
city: Beijing
country: China
facility: Site CN108
city: Beijing
country: China
facility: Site CN109
city: Beijing
country: China
facility: Site CN110
city: Beijing
country: China
facility: Site CN131
city: Changchun
country: China
facility: Site CN116
city: Changsha
country: China
facility: Site CN120
city: Fuzhou
country: China
facility: Site CN119
city: Guangzhou
country: China
facility: Site CN102
city: Guangzhou
country: China
facility: Site CN114
city: Guangzhou
country: China
facility: Site CN121
city: Guiyang City
country: China
facility: Site CN130
city: Hangzhou
country: China
facility: Site CN107
city: Hefei
country: China
facility: Site CN118
city: Huangpu Qu
country: China
facility: Site CN123
city: Jinan
country: China
facility: Site CN117
city: Lanzhou
country: China
facility: Site CN133
city: Nanjing
country: China
facility: Site CN128
city: Qingdao
country: China
facility: Site CN106
city: Shanghai
country: China
facility: Site CN126
city: Shanghai
country: China
facility: Site CN129
city: Shenyang
country: China
facility: Site CN125
city: Tianjin
country: China
facility: Site CN101
city: Wuhan
country: China
facility: Site CN105
city: Xi'an
country: China
facility: Site CN122
city: Zhangzhou
country: China
facility: Site CN132
city: Zhengzhou
country: China
facility: Site CN113
city: Zhengzhou
country: China
facility: Site CN136
city: Ampang
country: Malaysia
facility: Site MY306
city: George Town
country: Malaysia
facility: Site MY305
city: Johor Bahru
country: Malaysia
facility: Site MY301
city: Kota Kinabalu
country: Malaysia
facility: Site MY304
city: Kuala Lumpur
country: Malaysia
facility: Site MY302
city: Pulau Pinang
country: Malaysia
facility: Site MY303
city: Kemerovo
country: Russian Federation
facility: Site RU506
city: Krasnoyarsk
country: Russian Federation
facility: Site RU504
city: Moscow
country: Russian Federation
facility: Site RU508
city: Moscow
country: Russian Federation
facility: Site RU509
city: Saint Petersburg
country: Russian Federation
facility: Site RU501
city: Saint Petersburg
country: Russian Federation
facility: Site RU507
city: Saint-Petersburg
country: Russian Federation
facility: Site RU502
city: Singapore
country: Singapore
facility: Site SG401
city: Singapore
country: Singapore
facility: Site SG402
city: Singapore
country: Singapore
facility: Site SG403
city: Bangkok
country: Thailand
facility: Site TH203
city: Bangkok
country: Thailand
facility: Site TH205
city: Chiang Mai
country: Thailand
facility: Site TH204
city: Khon Kaen
country: Thailand
facility: Site TH201
city: Khon Kaen
country: Thailand
facility: Site TH202
Study officials:
affiliation: Astellas Pharma Inc
name: Medical Director
role: STUDY_DIRECTOR
References: