Phase 3 Open-label, Multicenter, Randomized Study of XY0206 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase 3(FLT3)-Internal Tandem Duplication（ITD） Mutation
Overview
- Phase
- Phase 3
- Status
- Not yet recruiting
- Sponsor
- Shijiazhuang Yiling Pharmaceutical Co. Ltd
- Enrollment
- 312
- Primary Endpoint
- Interim analysis: Complete remission(CR)/CR with partial hematologic recovery(CRh) rate in the experimental group.
Overview
Brief Summary
The purpose of this study is to determine the clinical benefit of XY0206 therapy in participants with FLT3-ITD mutated AML who are refractory to or have relapsed after prior AML therapy as shown with overall survival (OS) compared to salvage chemotherapy. In addition, this study is also to investigate the efficacy of XY0206 as assessed by CR/CRh rate in these subjects。
Detailed Description
Participants considered an adult according to local regulations at the time of signing informed consent will be randomized in a 2:1 ratio to receive XY0206 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),azacitidine, fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) or mitoxantrone, etoposide and cytarabine (MEC) . The randomization will be stratified by remission from previous treatment and preselected salvage chemotherapy. Participants will be administered treatment over continuous 28-day cycles.
Participants who have a donor identified and with complete remission after treatment may undergo hematopoietic stem cell transplant (HSCT) without leaving the study.
After treatment discontinuation, participants will have a end-of-treatment visit within 7 days after treatment discontinuation, followed by a 30-day follow-up for safety. After that, long term follow-up will be done every 90 days.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Age≥18 years old.
- •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 prior AML therapy (with or without hematopoietic stem cell transplant ):
- •Advanced relapse after first-line AML therapy is defined as: the patients achieved Complete remission without minor residual diseases/complete remission/complete remission with partial hematologic recovery/complete remission with incomplete hematologic recovery/complete remission with incomplete platelet recovery/Morphologic leukemia- free state(CRMRD-/CR/CRh/CRi/CRp/MLFS )after first-line treatment and relapsed after 12 months with hematological relapse;
- •Patients with relapsed / refractory AML.
- •Refractory to first-line AML therapy is defined as:the patient did not achieve CRMRD-/CR/CRh/CRi/CRp/MLFS 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.
- •Early relapse:Relapse within 12 months after consolidation therapy after achieving CRMRD-/CR/CRh/CRi/CRp/MLFS.
- •Relapse after 12 months but nonresponse to conventional chemotherapy after achieving CRMRD-/CR/CRh/CRi/CRp/MLFS.
- •Second or more relapse.
- •Patients who cannot tolerate intensive chemotherapy develop disease progression during continuous treatment with low-intensity drugs.
Exclusion Criteria
- •Patient was diagnosed as acute promyelocytic leukemia (APL), or Philadelphia chromosome（BCR-ABL）-positive leukemia (chronic myelogenous leukemia in blast crisis).
- •Patients who received live vaccine (including live attenuated vaccine) within 4 weeks before randomization and/or planed to receive live vaccine after enrollment.
- •Presence of FLT3-tyrosine kinase domain(TKD) mutation.
- •Patients were prior failed adequate treatment with FLT3 inhibitors.
- •AML with Central Nervous System Leukemia.
- •Patient has AML secondary to prior chemotherapy for other neoplasms, except for MDS.
- •Patients with other malignant tumors past or present,unless whose Disease-free survival period≥5 years.Non-melanin skin cancer, carcinoma in situ, or cervical intraepithelial neoplastic lesions with completed radical treatment (regardless of disease-free survival),and subjects with prostate cancer confined to the prostate and with no evidence of disease recurrence or progression,if they have started hormonal therapy or have undergone surgery to remove the malignancy or have undergone radical radiotherapy,will be eligible for the study.
- •Pretrial treatment conditions:
- •Patients who received hematopoietic stem cell transplantation within the 2 months before enrollment,or having clinically significant graft-versus-host disease (GVHD) or receiving systemic cortisol hormone therapy for GVHD.
- •Patients who received chemotherapy, biological therapy, targeted anti-tumor therapy within 14 days before the first use of the drug in this study or within 5 half-lives of the drug, or radiation therapy within 28 days.
Arms & Interventions
XY0206
XY0206 will be administered orally once a day in continuous 28-day cycles.
Intervention: XY0206 (Drug)
Salvage chemotherapy
Participants will receive salvage chemotherapy in 28-day cycles. Participants on Low-Dose Cytarabine (LoDAC) received 20 mg of cytarabine twice daily by subcutaneous (SC) injection for 10 days. Participants on azacitidine will receive 75 mg/m^2 daily by SC or IV injection for 7 days.Participants on fludarabine, cytarabine and granulocyte colony-stimulating factor (G-CSF) (FLAG) will receive 30 mg/m^2 of fludarabine daily by IV for 5 days (day 2 to 6), 1~2 g/m2 of cytarabine daily by IV for 5 days (day 2 to 6), and 300 μg/m^2 of G-CSF daily by SC or IV for 5 days (days 1 to 5). After completion of chemotherapy, G-CSF will be administered continually until absolute neutrophil count(ANC)>0.5 x 10^9 / L. Participants on mitoxantrone, etoposide, cytarabine(MEC) will receive 8 mg/m^2 of mitoxantrone daily by IV for 3 days (day 1 to 3), 100 mg/m2 of etoposide daily by IV for 7 days (day 1 to 7), and 100 mg/m^2 of cytarabine daily by IV for 7 days (days 1 to 7)
Intervention: Salvage Chemotherapy (Drug)
Outcomes
Primary Outcomes
Interim analysis: Complete remission(CR)/CR with partial hematologic recovery(CRh) rate in the experimental group.
Time Frame: up to 3 years.
The complete remission and complete remission with partial hematological recovery (CR/CRh) rate was defined as the number of subjects who achieved either CR or CRh at any of the postbaseline visits divided by the number of subjects in the analysis population.
The final analysis: Overall Survival(OS).
Time Frame: up to 3 years .
Overall survival was defined as the time from the date of randomization until the date of death from any cause.
Secondary Outcomes
- Key secondary end point: Event-Free Survival (EFS).(up to 3 years.)
- CR rate.(up to 3 years.)
- Duration of remission (DOR).(up to 3 years.)
- Composite complete remission rate.(up to 3 years.)
- Key secondary end point: CR/CRh rate .(up to 3 years.)
- Transplantation rate.(up to 3 years.)
- Population pharmacokinetic of XY0206.(Cycle 1 Day 15: predose and up to 4 hours post-dose; Day 28 predose of subsequent cycles. A cycle is 28 days.)
- minimal residual disease(MRD) negative rate(up to 3 years.)
- Safety assessed by adverse events.(up to 3 years.)
- Time to remission(TTR).(up to 3 years.)